Anatomical approaches were used to describe the distribution, appearance, and synaptic interactions of serotonin (5-HT)-immunoreactive axons in monkey prefrontal cortex. A plexus of 5-HT axons was found throughout the gray matter, with an especially high density in layer I and a slight increase in layer IV. They were strikingly heterogeneous, with a gradient of morphologies ranging from fine and nonvaricose to highly varicose or thick and nonvaricose. Electron microscopy showed that both varicose and nonvaricose axons were typically filled with clear vesicles and less abundant dense core vesicles. A serial section analysis of 5-HT varicosities in layers I, III, and V showed consistent results across layers. Only about 23% of labeled varicosities formed identifiable synapses. These synapses were consistently asymmetric and were 2-5 serial sections (or 0.08-0.38 mu) in diameter. Targets of identified 5-HT synapses were dendritic shafts with the exception of one cell soma. Followed in serial sections, postsynaptic dendrites typically had morphological features of interneurons, i.e. they lacked spines, had a high density of synaptic inputs, and often had a varicose morphology. Only 8% of postsynaptic shafts were classified as pyramidal dendrites. This is in striking contrast to our previous study in this cortex of dopamine axons, which synapsed predominantly on pyramidal dendrites. These are the first results to indicate that interneurons are the major recipient of identifiable 5-HT synapses in the monkey prefrontal cortex.